Process for the preparation of 2-or-9-oxa-3, 7-diazabicyclo (3.3.1) nonanes from 2-aminomethyl-2, 3-dihydrooxazines intermediates therefore, and processes for preparing such intermediates

ABSTRACT

There is provided a process for the preparation of a compound of formula (I), which process comprises reaction of a compound(of formula (II), with either: (a) a formaldehyde and a compound of formula (III), R a —OH and/or (b) a protected derivative of formaldehyde, wherein R 1 , R 2  and R a  have meanings given in the description.

FIELD OF THE INVENTION

This invention relates to a novel process for the preparation ofoxabispidine compounds.

BACKGROUND

The number of documented compounds including the9-oxa-3,7-diazabicyclo-[3.3.1]nonane (oxabispidine) structure is veryfew. As a result, there are very few known processes that arespecifically adapted for the preparation of oxabispidine compounds.

Certain oxabispidine compounds are disclosed in Chem. Ber. 96(11), 2827(1963) as intermediates in the synthesis of 1,3diaza-6-oxa-adamantanes.

Hemiacetals (and related compounds) having the oxabispidine ringstructure are disclosed in J. Org. Chem 31, 277 (1966), ibid 61(25),8897 (1996), ibid 63(5), 1566 (1998) and ibid. 64(3), 960 (1999) asunexpected products from the oxidation of 1,5-diazacyclooctane-1,3-diolsor the reduction of 1,5-diazacyclooctane-1,3-diones.

1,3-Dimethyl-3,7-ditosyl-9-oxa-3,7azabicyclo[3.3.1]nonane is disclosedin J. Org. Chem 32, 2425 (1967) as a product from the attemptedacetylation oftrans-1,3-dimethyl-1,5-ditosyl-1,5-diazacyclooctane-1,3-diol.

International patent application WO 01/28992 describes the synthesis ofa wide range of oxabispidine compounds, which compounds are indicated asbeing useful in the treatment of cardiac arrhythmias. In WO 01/28992,processes for the formation of the oxabispidine ring system aredisclosed, which processes all involve the formation of oxabispidineprecursors in mixtures of cis and trans isomers. Such processes have thedisadvantage that only one of those two isomers may be reacted to givethe desired oxabispidine ring system.

None of the above-mentioned documents disclose or suggest the synthesisof oxabispidine compounds via 2,3-dihydrooxazines. We have now found,surprisingly, that oxabispidine compounds may be prepared convenientlyby way of the cyclisation of 2-aminomethyl-substituted2,3-dihydrooxazines.

DISCLOSURE OF THE INVENTION

According to a first aspect of the invention there is provided a processfor the preparation of a compound of formula I,

wherein

-   -   R¹ represents H, aryl or a structural fragment of formula Ia,        in which    -   R³ represents H, halo, C₁₋₆ alkyl, —OR⁶, -E-N(R⁷)R⁸ or, together        with R⁴, represents ═O;    -   R⁴ represents H, C₁₋₆ alkyl or, together with R³, represents ═O;    -   R⁶ represents H, C₁₋₆ alkyl, -E-aryl, -E-Het¹, —C(O)R^(9a),        —C(O)OR^(9b) or —C(O)N(R^(10a))R^(10b);    -   R⁷ represents H, C₁₋₆ alkyl, -E-aryl, -E-Het¹, —C(O)R^(9a),        —C(O)OR^(9b), —S(O)₂R^(9c), —[C(O)]_(p)N(R^(10a))R^(10b) or        —C(NH)NH₂;    -   R⁸ represents H, C₁₋₆ alkyl, -E-aryl or —C(O)R^(9d);    -   R^(9a) to R^(9d) independently represent, at each occurrence,    -   C₁₋₆ alkyl (optionally substituted and/or terminated by one or        more substituents selected from halo, aryl and Het²), aryl, Het,        or R^(9a) and R^(9d) independently represent H;    -   R^(10a) a R^(10b) independently represent, at each occurrence, H        or C₁₋₆ alkyl (optionally substituted and/or terminated by one        or more substituents selected from halo, aryl and Het⁴), aryl,        Het⁵, or together represent C₃₋₆ alkylene, optionally        interrupted by an O atom;    -   E represents, at each occurrence, a direct bond or C₁₋₄        alkylene;    -   p represents 1 or 2;    -   A represents -G-, -J-N(R¹¹)— or -J-O— (in which latter two        groups, N(R¹¹)— or O— is attached to the carbon atom bearing R³        and R⁴);    -   B represents -Z-, -Z-N(R¹²)—, —NR¹²)-Z-, -Z-S(O)_(n)— or -Z-O—        (in which latter two groups, Z is attached to the carbon atom        bearing R³ and R⁴);    -   G represents a direct bond or C₁₋₆ alkylene;    -   J represents C₂₋₆ alkylene;    -   Z represents a direct bond or C₁₋₄ alkylene;    -   R¹¹ and R¹² independently represent H or C₁₋₆ alkyl;    -   n represents 0, 1 or 2;    -   R⁵ represents aryl or heteroaryl, both of which groups are        optionally substituted by one or more substituents selected from        —OH, cyano, halo, nitro, C₁₋₆ alkyl (optionally terminated by        —N(H)C(O)OR^(13a)), C₁₋₆ alkoxy,    -   —N(R^(14a))R^(14b), —C(O)R^(14c), —C(O)OR^(14d),        —C(O)N(R^(14e))R^(14f), —N(R^(14g))C(O)(R^(14h),    -   —N(R^(14i))C(O)N(R^(14j))R^(14k), —N(R^(14m))S(O)₂R^(13b),        —S(O)₂R^(13c) and/or    -   —OS(O)₂R^(13d);    -   R^(13a) to R^(13d) independently represent C₁₋₆ alkyl;    -   R^(14a) and R^(14b) independently represent H, C₁₋₆ alkyl or        together represent C₃₋₆ alkylene, resulting in a four- to        seven-membered nitrogen-containing ring;    -   R^(14c) to R^(14m) independently represent H or C₁₋₆ alkyl;    -   Het¹ to Het⁵ independently represent, at each occurrence, five-        to twelve-membered heteroaryl groups containing one or more        heteroatoms selected from oxygen, nitrogen and/or sulfur, which        heterocyclic groups are optionally substituted by one or more        substituents selected from ═O, —OH, cyano, halo, nitro, C₁₋₆        alkyl, C₁₋₆ alkoxy, aryl, aryloxy, —N(R^(15a))R^(15b),        —C(O)R^(15c), —C(O)OR^(15d), —C(O)N(R^(15e))R^(15f),        —N(R^(15g))C(O)R^(15h) and —N(^(15i))S(O)₂R^(15j);    -   R^(15a) to R^(15j) independently represent C₁₋₆ alkyl, aryl or        R^(15a) to R^(15i) independently represent H; and    -   wherein each aryl and aryloxy group, unless otherwise specified,        is optionally substituted; provided that:    -   (a) when R⁴ represents H or C₁₋₄ alkyl; and        -   A represents -J-N(R¹¹) or -J-O—;        -   then B does not represent —N(R¹²)—, —S(O)_(n)—, —O— or            —N(R¹²)-Z- (in which latter group —N(R¹²) is attached to the            carbon atom bearing R³ and R⁴);    -   (b) when R³ represents —OR⁶ or -E-N(R⁷)R⁸ in which E represents        a direct bond, then:        -   (i) A does not represent a direct bond, -J-N(R¹¹)— or -J-O—;            and        -   (ii) B does not represent —N(R¹²)—, —S(O)_(n)—, —O— or            —N(R¹²)-Z- (in which latter group —N(R¹²) is attached to the            carbon atom bearing R³ and R⁴);    -   (c) when A represents a direct bond, then R³ and R⁴ do not        together represent ═O;    -   R² represents an electron withdrawing amino protecting group;        and    -   R^(a) represents C₁₋₄ alkyl or benzyl,    -   which process comprises reaction of a compound of formula II,        wherein R¹ and R² are as defined above, with either:    -   (a) a formaldehyde and a compound of formula III,        R^(a)—OH   III        wherein R^(a) is as defined above; and/or    -   (b) a protected derivative of a formaldehyde,    -   which process is referred to hereinafter as “the process of the        invention”.

A preferred process of the invention involves the reaction of a compoundof formula II as hereinbefore defined with a formaldehyde and a compoundof formula III as hereinbefore defined.

Unless otherwise specified, alkyl groups and alkoxy groups as definedherein may be straight-chain or, when there is a sufficient number (i.e.a minimum of three) of carbon atoms be branched-chain, and/or cyclic.Further, when there is a sufficient number (i.e. a minimum of four) ofcarbon atoms, such alkyl and alkoxy groups may also be partcyclic/acyclic. Such alkyl and alkoxy groups may also be saturated or,when there is a sufficient number (i.e. a minimum of two) of carbonatoms, be unsaturated and/or interrupted by one or more oxygen and/orsulfur atoms. Unless otherwise specified, alkyl and alkoxy groups mayalso be substituted by one or more halo, and especially fluoro, atoms.

Unless otherwise specified, alkylene groups as defined herein may bestraight-chain or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be branched-chain. Such alkylene chains may alsobe saturated or, when there is a sufficient number (i.e. a minimum oftwo) of carbon atoms, be unsaturated and/or interrupted by one or moreoxygen and/or sulfur atoms. Unless otherwise specified, alkylene groupsmay also be substituted by one or more halo (e.g. fluoro) atoms.

The term “aryl”, when used herein, includes C₆₋₁₀ aryl groups such asphenyl, naphthyl and the like. The term “aryloxy”, when used hereinincludes C₆₋₁₀ aryloxy groups such as phenoxy, naphthoxy and the like.For the avoidance of doubt, aryloxy groups referred to herein areattached to the rest of the molecule via the O-atom of the oxy-group.Unless otherwise specified, aryl and aryloxy groups may be substitutedby one or more substituents including —OH, cyano, halo, nitro, C₁₋₆alkyl, C₁₋₆ alkoxy, —N(R^(14a))R^(14b), —C(O)R^(14c), —C(O)OR^(14d),—C(O)N(R^(14e))R^(14f), —N(R^(14g))C(O)R^(14h), —N(R^(14m))S(O)₂R^(13b),—S(O)₂R^(13c) and/or —OS(O)₂R^(13d) (wherein R^(13b) to R^(13d) andR^(14a) to R^(14m) are as hereinbefore defined). When substituted, aryland aryloxy groups are preferably substituted by between one and threesubstitutents.

Heteroaryl groups that may be mentioned include those containing 1 to 4heteroatoms (selected from the group oxygen, nitrogen and/or sulfur) andin which the total number of atoms in the ring system are between fiveand twelve. Heteroaryl groups may be fully saturated, wholly aromatic,partly aromatic and/or bicyclic in character. Heteroaryl groups that maybe mentioned include benzodioxanyl, benzodioxepanyl, benzodioxolyl,benzofuranyl, benzimidazolyl, benzomorpholinyl, benzoxazinonyl,benzothiophenyl, chromanyl, cinnolinyl, dioxanyl, furanyl, imidazolyl,imidazo[1,2-a]pyridinyl, indolyl, isoquinolinyl, isoxazolyl,morpholinyl, oxazolyl, phthalazinyl, piperazinyl, piperidinyl, purinyl,pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimindinyl, pyrrolidinonyl,pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,tetrahydropyranyl, tetrahydrofuiranyl, thiazolyl, thienyl,thiochromanyl, triazolyl and the like. Substituents on heteroaryl groupsmay, where appropriate, be located on any atom in the ring systemincluding a heteroatom. The point of attachment of heteroaryl groups tothe rest of the molecule may be via any atom in the ring systemincluding (where appropriate) a heteroatom, or an atom on any fusedcarbocyclic ring that may be present as part of the ring system.Heteroaryl groups may also be in the N- or S-oxidised form. When R⁵ is aheteroaryl group, preferred heteroaryl groups include pyridinyl groups.

The term “halo”, when used herein, includes fluoro, chloro, bromo andiodo.

As used herein, the term “amino protecting group” includes groupsmentioned in “Protective Groups in Organic Synthesis”, 2^(nd) edition, TW Greene & P G M Wutz, Wiley-Interscience (1991), in particular thoseindexed at the start of the chapter entitled “Protection for the AminoGroup” (see pages 309 to 315) of that reference, the disclosure in whichdocument is hereby incorporated by reference.

Specific examples of amino protecting groups thus include:

-   -   (a) those which form carbamate groups (e.g. to provide methyl,        cyclopropylmethyl, 1-methyl-1-cyclopropylmethyl,        diisopropyl-methyl, 9-fluorenylmethyl,        9-(2-sulfo)fluorenylmethyl, 2-furanylmethyl,        2,2,2-trichloroethyl, 2-haloethyl, 2-trimethylsilylethyl,        2-methylthioethyl, 2-methyl-sulfonylethyl,        2(p-toluenesulfonyl)ethyl, 2-phosphonioethyl,        1,1-dimethylpropynyl,        1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl,        1,1-dimethyl-3-(N,N-diethylamino)-propyl,        1-methyl-1-(1-adamantyl)ethyl, 1-methyl-1-phenylethyl,        1-methyl-1-(3,5-di-methoxyphenyl)ethyl,        1-methyl-1-(4-biphenylyl)-ethyl,        1-methyl-1-(p-phenylazophenyl)ethyl, 1,1-dimethyl-2-haloethyl,        1,1-dimethyl-2,2,2-trichloroethyl, 1,1-dimethyl-2-cyanoethyl,        isobutyl, t-butyl, t-amyl, cyclobutyl, 1-methylcyclobutyl,        cyclopentyl, cyclohexyl, 1-methylcyclohexyl, 1-adamantyl,        isobornyl, vinyl, allyl, cinnamyl, phenyl,        2,4,6-tri-t-butylphenyl, m-nitrophenyl, S-phenyl, 8-quinolinyl,        N-hydroxypiperidinyl, 4-(1,4-dimethylpiperidinyl),        4,5-diphenyl-3-oxazolin-2-one, benzyl, 2,4,6-methylbenzyl,        p-methoxybenzyl,        3,5-dimethoxybenzyl,p-decyloxybenzyl,p-nitro-benzyl,        o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,p-bromobenzyl,        chlorobenzyl, 2,4-dichloro-benzyl,p-cyanobenzyl,        o-(N,N-dimethyl-carboxamidobenzyl)benzyl,        m-chloro-p-acyloxybenzyl, p-(dihydroxy-boryl)benzyl,        p-(phenylazo)benzyl, p-(p′-methoxyphenylazo)benzyl,        5-benzisoxazolylmethyl, 9-anthrylmethyl, diphenylmethyl,        phenyl(o-nitrophenyl)methyl, di(2-pyridyl)methyl,        1-methyl-1-(4-pyridyl)-ethyl, isonicotinyl, or S-benzyl,        carbamate groups);    -   (b) those which form amide groups (e.g. to provide N-formyl,        N-acetyl, N-chloroacetyl, N-dichloroacetyl, N-trichloroacetyl,        N-trifluoroacetyl, N-o-nitrophenylacetyl,        N-o-nitrophenoxyacetyl, N-acetoacetyl, N-acetylpyridinium,        N-3-phenylpropionyl, N-3-(p-hydroxyphenyl)-propionyl,        N-3-(o-nitrophenyl)propionyl,        N-2-methyl-2-(o-nitrophen-oxy)propionyl,        N-2-methyl-2-(o-phenylazophenoxy)propionyl, N4-chlorobutyryl,        N-isobutyryl, N-o-nitrocinnamoyl, N-picolinoyl,        N-(N′-acetylmethionyl), N-(N′-benzoylphenylalanyl), N-benzoyl,        N-p-phenylbenzoyl, N-p-methoxybenzoyl, N-o-nitrobenzoyl, or        N-o-(benzoyloxymethyl)benzoyl, amide groups);    -   (c) alkyl groups (e.g. N-allyl, N-phenacyl, N-3-acetoxypropyl,        N-(4-nitro-1-cyclohexyl-2-oxo-pyrrolin-3-yl), N-methoxymethyl,        N-chloroethoxymethyl, N-benzyloxymethyl, N-pivaloyloxymethyl,        N-2-tetrahydropyranyl, N-2,4-dinitrophenyl, N-benzyl,        N-3,4-di-methoxybenzyl, N-o-nitrobenzyl,        N-di(p-methoxyphenyl)methyl, N-triphenylmethyl,        N-(p-methoxyphenyl)diphenylmethyl, N-diphenyl-4-pyridylmethyl,        N-2-picolyl N′-oxide or N-dibenzosuberyl groups);    -   (d) phosphinyl and phosphoryl groups (e.g. N-diphenylphosphinyl,        N-dimethylthiophosphinyl, N-diphenylthiophosphinyl,        N-diethyl-phosphoryl, N-dibenzylphosphoryl or N-phenylphosphoryl        groups);    -   (e) sulfenyl groups (e.g. N-benzenesulfenyl,        N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl,        N-pentachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulfenyl        or N-triphenylmethylsulfenyl groups);    -   (f) sulfonyl groups (e.g. N-benzenesulfonyl,        N-p-methoxybenzene-sulfonyl, N-2,4,6-trimethylbenzenesulfonyl,        N-toluenesulfonyl, N-benzylsulfonyl, N-p-methylbenzylsulfonyl,        N-trifluoromethylsulfonyl or N-phenacylsulfonyl); and    -   (g) the N-trimethylsilyl group.

Electron-withdrawing amino protecting groups include the sulfonyl groupsmentioned above, as well as those which form amide or, particularly,carbamate groups mentioned above, such as tert-butoxycarbonyl (toprovide a tert-butyl carbamate group) and, particularly,benzyloxycarbonyl (to provide a benzyl carbamate group).

The skilled person will also appreciate that certain values of thestructural fragment of formula Ia may also be referred to as aminoprotecting groups (see e.g. group (c) in the list above).

Suitable formaldehydes for use in the process of the invention includeparaformaldehyde. Suitable protected derivatives of formaldehyde includethose that are protected at the carbonyl group (e.g. as C₁₋₄ alkylacetals, such as methyl acetals) and that react with the compound offormula II to give an intermediate that is capable of undergoingcyclisation to give a compound of formula I.

Preferred values of R¹ include H or structural fragments of formula Iain which:

-   -   R³ represents H, methyl, —OR⁶ or —N(H)R⁷;    -   R⁴ represents H or methyl;    -   R⁶ represents H, C₁₋₂ alkyl or phenyl (which phenyl group is        optionally substituted by one or more substituents selected from        cyano and C₁₋₄ alkoxy);    -   R⁷ represents H, C₁₋₂ alkyl, phenyl (which phenyl group is        optionally substituted by one or more substituents selected from        cyano, halo, nitro, C₁₋₄ alkyl and C₁₋₄ alkoxy), —C(O)R^(9a) or        —C(O)OR^(9b);    -   R^(9a) and R^(9b) independently represent C₁₋₆ alkyl;    -   A represents a direct bond or C₁₋₄ alkylene;    -   B represents -Z-, -Z-N(R¹²)—, -Z-S(O)₂— or -Z-O—;    -   R¹² represents H or methyl;    -   R⁵ represents pyridinyl or phenyl, which latter group is        optionally substituted by one to three substituents selected        from cyano, nitro, C₁₋₂ alkoxy, NH₂ and —N(H)S(O)₂CH₃.

More preferred values of R¹ include H or structural fragments of formulaIa in which:

-   -   R³ represents H, —OR⁶ or —N(H)R⁷;    -   R⁴ represents H;    -   R⁶ represents H or phenyl (optionally substituted by one or more        substituents selected from cyano and C₁₋₂ alkoxy);    -   R⁷ represents H, phenyl (optionally substituted by one or more        cyano groups) or —C(O)O—C₁₋₅ alkyl;    -   A represents a single bond or C₁₋₃ alkylene;    -   represents -Z-, -Z-N(H)—, -Z-S(O)₂— or -Z-O—;    -   R⁵ represents phenyl optionally substituted by cyano in the        ortho- and/or, in particular, the para-position relative to B.

Particularly preferred values of R¹ include structural fragments offormula Ia in which:

-   -   R³ represents H;    -   A represents methylene, ethylene or, especially, a single bond;    -   B represents a single bond;    -   R⁵ represents unsubstituted phenyl.

Preferred values of R^(a) include ethyl and, particularly, methyl.

The process of the invention is preferably carried out under one or moreof the following conditions.

-   -   (a) In the presence of a suitable solvent system. Suitable        solvents include polar and/or hydroxylic solvents such as        acetonitrile, C₁₋₄ alkyl alcohols, toluene and mixtures thereof.    -   (b) In the presence of a suitable catalyst (e.g. an acidic        catalyst such as a Lewis acid or a Brönsted acid (e.g. a        sulfonic acid such as p-toluenesulfonic acid)).    -   (c) At or above room temperature (e.g. from room temperature to        the reflux temperature of the solvent system that is employed).        When the solvent that is employed is a mixture of a C₁₋₄ alkyl        alcohol (such as methanol) and acetonitrile, reaction is        preferably carried out at reflux.    -   (d) Using one or more equivalents (relative to the compound of        formula II) of the formaldehyde (and/or a suitable protected        derivative thereof), for example between 1 and 10 equivalents        (such as between 1 and 5 (e.g. between 2 and 4) equivalents).    -   (e) Using one or more equivalents (relative to the compound of        formula II) of the compound of formula III (e.g. an excess such        as 10 or more equivalents).    -   (f) By reacting the compound of formula II with one or more        (e.g. three) equivalents of a formaldehyde (e.g.        paraformaldehyde), in the presence of an excess of a compound of        formula III.

The process of the invention is preferably carried out to providecompounds of formula I in which R¹ represents benzyl and R² representsbenzyloxycarbonyl.

Compounds of formula II may be prepared by methods known to thoseskilled in the art. For example, compounds of formula II, andderivatives thereof, may be prepared by elimination of an alcohol from acorresponding 6-aminomethyl-substituted 2-alkoxymorpholine.

For example, compounds of formula II may be prepared by elimination ofR^(b)OH from a compound of formula IV,

wherein

-   -   R^(1a) represents an aryl group, a structural fragment of        formula Ia as hereinbefore defined, an electron withdrawing        amino protecting group as hereinbefore defined, or, together        with R^(1b), represents a cyclic amino protecting group;    -   R^(1b) represents an electron withdrawing amino protecting group        as hereinbefore defined, or, together with R^(1a), represents a        cyclic amino protecting group;    -   R^(b) represents C₁₋₄ alkyl; and    -   R² is as hereinbefore defined,    -   followed by deprotection (as necessary) of the nitrogen atom to        which the groups R^(1a) and R^(1b) are attached and then, if        necessary (i.e. in cases where the group R^(1a), in the compound        of formula IV formed by way of the elimination step, does not        represent an aryl group or a structural fragment of formula Ia),        reaction of the deprotected amine with a compound that provides        the aryl group or the structural fragment of formula la as        hereinbefore defined. The term “cyclic amino protecting group”        will be understood by those skilled in the art to include all        amino protecting groups that, when bound to the nitrogen atom of        the amino group, form a cyclic system incorporating that        nitrogen atom. The term therefore includes groups that form        cyclic imido groups, such as succinimide and, particularly,        phthalimide groups.

As before, the term “electron-withdrawing amino protecting group”includes those which form carbamate and amide groups, as well asphosphoryl and sulfonyl groups, mentioned hereinbefore in relation tothe term “amino protecting group”. Preferred electron-withdrawing aminoprotecting groups that R² may represent in compounds of formula IVinclude those which form carbamate groups, e.g. benzyloxycarbonyl.

Preferred values of R^(b) include ethyl and, particularly, methyl.

It is preferred that elimination of R^(b)OH from a compound of formulaIV (hereinafter referred to as the “elimination process”) is carried outon a compound of formula IV in which R^(1a) and R^(1b) togetherrepresent a cyclic amino protecting group. Preferred cyclic aminoprotecting groups thus include those which form cyclic imido groups suchas phthalimide groups.

The elimination process is preferably carried out under one or more ofthe following conditions:

-   -   (a) In the presence of a suitable solvent system. Suitable        solvents include those that are capable of facilitating        elimination of R^(b)OH and yet will not react with the iminium        ion intermediate, such as an aromatic hydrocarbon, e.g. toluene.    -   (b) In the presence of a suitable catalyst (e.g. an acidic        catalyst such as a Lewis acid or a Brönsted acid (e.g. a        sulfonic acid such asp-toluenesulfonic acid)).    -   (c) At elevated temperature (e.g. from above room temperature to        around the reflux temperature of the solvent system that is        employed). When the solvent that is employed is toluene, the        reaction is preferably carried out at reflux.    -   (d) In the presence of an alcohol sorbing agent (e.g. molecular        sieves (such as 3Å molecular sieves)).

Following the elimination process, deprotection of the nitrogen atom towhich the groups R^(1a) and R^(1b) are attached (which may compriseremoval of both R^(1a) and R^(1b), or of R^(1b) alone) may be carriedout by way of routine techniques. For example, when R^(1a) and R^(1b)together represents a cyclic amino protecting group, such asphthalimide, deprotection may be carried out by way of reaction withhydrazine, for example as described hereinafter.

When the deprotection is followed by reaction with a compound thatprovides the structural fragment of formula Ia, the lattertransformation may be achieved using methods known to those skilled inthe art, for example by analogy with coupling, and protection (e.g. inthe case where the structural fragment Ia may be described as aprotecting group, such as a benzyl group), methods disclosed in WO01/28992. For example, this may be carried out by reaction of a compoundof formula II in which R¹ represents H with a compound of formula V,R⁵BC(R³)(R⁴)AL¹   Vwherein L¹ represents a suitable leaving group, such as halo,alkanesulfonate (e.g. mesylate), perfluoroalkanesulfonate orarenesulfonate (e.g. 2- or 4-nitrobenzenesulfonate, toluenesulfonate orbenzenesulfonate) and A, B, R³, R⁴ and R⁵ are as hereinbefore defined,under reaction conditions that are well known to those skilled in theart, for example at elevated temperature (e.g. between 35° C. and refluxtemperature) in the presence of a suitable base (e.g. triethylamine orpotassium carbonate) and an appropriate organic solvent (e.g.acetonitrile, dichloromethane, chloroform, dimethylsulfoxide,N,N-dimethylformamide, a lower alkyl alcohol (e.g. ethanol), isopropylacetate or mixtures thereof). In the case of compounds of formula II inwhich R¹ represents a benzyl group, such compounds may also be made byreaction of the deprotected amine with benzaldehyde, followed byreduction of the resultant intermediate (e.g. as described hereinafter).

Compounds of formula IV may be prepared by methods known to thoseskilled in the art. For example, compounds of formula IV, or derivativesthereof, may be prepared by cyclisation of compound of formula VI,

wherein

-   -   R^(2a) represents an amino protecting group as hereinbefore        defined; and    -   R^(1a), R^(1b) and R^(b) are as hereinbefore defined, followed        by, if necessary (i.e. in cases where R^(2a) does not represent        an electron-withdrawing amino protecting group as hereinbefore        defined), replacement of the amino protecting group R^(2a) by an        electron-withdrawing amino protecting group R².

Preferred values of R^(2a) include amino protecting groups mentionedhereinbefore and, particularly, alkylaryl groups such as C₁₋₃alkylphenyl and especially benzyl. In this respect, the abovecyclisation process is preferably carried out using a compound offormula VI in which R^(2a) represents alkylaryl, followed by replacementof that alkylaryl protecting group with an electron-withdrawingprotecting group R² as hereinbefore defined.

The cyclisation process is preferably carried out under one or more ofthe following conditions.

-   -   (a) In the presence of a suitable solvent system. Suitable        solvents include aromatic hydrocarbons (e.g. toluene), aliphatic        hydrocarbons (e.g. cyclohexane) and halogenated (e.g.        chlorinated) hydrocarbons such as chloroform and, particularly,        dichloromethane.    -   (b) In the presence of a suitable catalyst (e.g. an acidic        catalyst such as a Lewis acid or a Brönsted acid (e.g. a        sulfonic acid such asp-toluenesulfonic acid)).    -   (c) At or above room temperature (e.g. from room temperature to        the reflux temperature of the solvent system that is employed).        When the solvent that is employed is dichloromehane, the        reaction is preferably carried out at reflux.

The cyclisation process is preferably carried out to provide compoundsin which R^(1a) and R^(1b), together with the nitrogen atom to whichthey are attached, represent a cyclic imide such as a phthalimide group.

Further, the cyclisation process is preferably carried out on compoundsof formula VI in which R^(2a) represents an alkylaryl group, such asbenzyl, followed by replacement of that alkylaryl group with anelectron-withdrawing amino protecting group by analogy with methodsknown to those skilled in the art (e.g. by a deprotection/protectionprocedure, which is optionally carried out in one step). For example,compounds of formula IV in which R² represents benzyloxycarbonyl may beprepared by cyclisation of a corresponding compound of formula VI, inwhich R^(2a) represents an alkylaryl group followed by reaction of theresultant intermediate with benzylchloroformate, for example asdescribed hereinafter. Compounds of formula VI may be prepared bymethods known to those skilled in the art. For example, compounds offormula VI may be prepared by reaction of a compound of formula VII,

wherein R^(1a) and R^(1b) are as hereinbefore defined, with a compoundof formula VIII,

wherein R^(2a) and R^(2b) are as hereinbefore defined.

Preferred values of R^(1a, R) ^(1b), R^(2a), and R^(b) include thosementioned hereinbefore.

Reaction of compounds of formula VII with compounds of formula VIII maybe carried out under one or more of the following conditions:

-   -   (a) In the presence of a suitable solvent system. Suitable        solvents include polar molecules (e.g. a hydroxylic solvents        such as ethanol, methanol, propan-2-ol, or mixtures thereof        (such as industrial methylated spirit), DMSO, acetonitrile, DMF        etc.).    -   (b) At or above room temperature (e.g. from room temperature to        the reflux temperature of the solvent system that is employed).        When the solvent system that is employed is industrial        methylated spirit, reaction is preferably carried out at reflux.    -   c) Under an appropriate inert atmosphere (e.g. under nitrogen).    -   (d) Using a molar ratio of the compound of formula VII to the        compound of formula VIII of between 3:2 and 2:3 (e.g. between        11:10 and 10:11, such as 1:1).

Compounds of formula VI may, following their formation from compounds offormula VII and VIII, and without being isolated, be converted directly(i.e. in a “one-pot” procedure) to compounds of formula IV. Thisconversion may be achieved by addition of a suitable catalyst for thecyclisation reaction (e.g. an acidic catalyst such asp-toluenesulfonicacid) and/or by solvent exchange (e.g. from industrial methylatedspirits to toluene or dichloromethane). Once formed, compounds offormula I may be converted to other compounds of formula I (e.g. byconversion of one R¹ and/or R² group to another) or to other compoundscontaining the oxabispidine ring system.

Thus, there is further provided a process for the preparation of acompound of formula IX,

wherein R^(2b) represents H or R² and R¹ and R² are as hereinbeforedefined, which process comprises reduction of a corresponding compoundformula I, as hereinbefore defined, in the presence of a suitablereducing agent.

It is preferred that this reduction is carried out to produce compoundsof formula IX in which R^(2b) is H. Thus, the reduction is preferablycarried out using a compound of formula I in which R² represents anelectron-withdrawing amino protecting group that may be cleaved underreducing conditions (e.g. the benzyloxycarbonyl group).

Preferred values of R¹ include those mentioned hereinbefore.

Suitable reducing agents include DIBALH or one or more hydrogenationcatalysts in the presence of hydrogen. Suitable hydrogenation catalystsare known to those skilled in the art and include supported metalcatalysts such as Pt/C, Rh/C and, particularly, Pd/C.

When the reducing agent is a hydrogenation catalyst in the presence ofhydrogen, the formation of compounds of formula IX may be carried outunder one or more of the following conditions:

-   -   (a) In the presence of a suitable solvent system. Suitable        solvents include those comprising polar molecules (e.g.        acetonitrile or hydroxylic compounds such as ethanol or,        particularly, methanol, or mixtures thereof).    -   (b) At or above room temperature (e.g. from room temperature to        100° C.). When the solvent system that is employed is methanol,        reaction is preferably carried out at room (i.e. ambient)        temperature.    -   (c) At or above atmospheric pressure (e.g. between 100 and 400        kPa (1 to 4 bar), such as at 200 kPa).

Compounds of formulae III, V, VII and VIII, and derivatives thereof, areeither commercially available, are known in the literature or may beobtained by analogy with the processes described herein, or byconventional synthetic procedures, in accordance with standardtechniques, from readily available starting materials using appropriatereagents and reaction conditions. For example, compounds of formula VIIImay be prepared according to, or by analogy with, the methods disclosedin Chem. Pharm. Bull. 40(2), 343 (1992).

The skilled person will appreciate that certain compounds of formulae I,II and IX may be prepared from certain other compounds of formulae I, IIand IX, respectively, or from structurally related compounds.

In particular, compounds of formulae I, II or IX in which R¹ representscertain values of the structural fragment of formula Ia may be preparedfrom other compounds of formulae I, II or IX, 20 respectively, accordingto or by analogy with relevant processes known in the art for thesynthesis or interconversion of compounds containing correspondingstructural fragments of formula Ia. Such processes are described in, forexample, international patent applications WO 99/31100, WO 00/76997, WO00/76998, WO 00/76999, WO 00/77000 and, particularly, WO 01/28992.

Furthermore compounds of formula XI comprising amino protecting groupsat one or both of the bispidine nitrogens may be deprotected understandard conditions, simultaneously and/or sequentially, andsubsequently reacted with reagents to form compounds as describedgenerically and specifically in WO 01/28992. Particular compounds thatmay be mentioned in WO 01/28992 include:

-   -   4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile;        tert-butyl        2-{7-[3-(cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate;        tert-butyl        2-{7-[4(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate;        and tert-butyl        2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate        (the compounds of Examples 3, 7, 8 and 9, respectively, of that        document), which compounds may be prepared from compounds of        formula XI (e.g. a compound of formula XI in which R¹ represents        benzyl and R² represents H;        3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane; see Preparations        A(iii) and N(iv) of WO 01/28992), in accordance with the        processes described in WO 01/28992, the relevant disclosures of        which document (e.g. Preparations A, B, C, G and N and Examples        3, 7, 8 and 9) are hereby incorporated by reference.

It will be appreciated by those skilled in the art that, in theprocesses described above, the functional groups of intermediatecompounds may be, or may need to be, protected by protecting groups.Functional groups which it is desirable to protect include hydroxy andamino. Suitable protecting groups for hydroxy include trialkylsilyl anddiarylalkylsilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl andalkylcarbonyl groups (e.g. methyl- and ethylcarbonyl groups). Suitableprotecting groups for amino include the amino protecting groupsmentioned hereinbefore, such as benzyl, sulfonyl (e.g. benzenesulfonyl),tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl.

The protection and deprotection of functional groups may take placebefore or after any of the reaction steps described hereinbefore.

Protecting groups may be removed in accordance with techniques that arewell known to those skilled in the art and as described hereinafter.

The use of protecting groups is fully described in “Protective Groups inOrganic Chemistry”, edited by J. W. F. McOmie, Plenum Press (1973), and“Protective Groups in Organic Synthesis”, 3^(rd) edition, T. W. Greene &P. G. M. Wutz, Wiley-Interscience (1999).

Those skilled in the art will appreciate that the processes describedherein may be used to prepare compounds of formulae I, II, IV, VI and IXin any given stereochemical form.

The processes described herein may be utilised in the synthesis ofcompounds comprising the oxabispidine moiety. The processes possess thesurprising advantage that compounds of formula I (as well as compoundsof formulae II, IV, VI and IX) may be prepared in higher yields, in lesstime, more conveniently, and at a lower cost, than when preparedaccording to the process described in the prior art.

In particular, processes described herein may have the advantage that alower proportion of the monocyclic precursors of compounds of formula I(i.e., in the present case, the compound of formula II) is incapable offorming oxabispidine product as compared to the precursors employed inthe processes described in WO 01/28992. In this manner, the process ofthe invention may have the advantage that the production of compounds offormulae I and IX involves less wastage of unreactive intermediateproducts than the production of the same or similar compounds accordingto processes described in WO 01/28992.

Further, the elimination process described herein has the advantage thatit offers particularly in conjunction with the previous steps ofreaction of a compound of formula VII with a compound of formula VIII,and the cyclisation process as hereinbefore described) a concisesynthesis for the formation of 2,3-dihydrooxazines (such as2-aminomethyl-substituted 2,3-dihydrooxazines), which compounds areuseful in the synthesis of the oxabispidine ring system.

Moreover, the processes described herein have the advantage thatoxabispidine compounds may be produced without the use of protectinggroups that may have disadvantageous properties.

The invention is illustrated, but in no way limited, by the followingexamples.

EXAMPLES

General Experimental Procedures

Mass spectra were recorded on one of the following instruments: a WatersZMD single quad with electrospray (S/N mc350); a Perkin-Elmer SciX API150ex spectrometer; a VG Quattro II triple quadrupole; a VG Platform IIsingle quadrupole; or a Micromass Platform LCZ single quadrupole massspectrometer (the latter three instruments were equipped with apneumatically assisted electrospray interface (LC-MS)). ¹H NMR and ¹³CNMR measurements were performed on Varian 300, 400 and 500spectrometers, operating at ¹H frequencies of 300, 400 and 500 Mrespectively, and at ¹³C frequencies of 75.5, 100.6 and 125.7 MHzrespectively.

Rotamers may or may not be denoted in spectra depending upon ease ofinterpretation of spectra Unless otherwise stated, chemical shifts aregiven in ppm with the solvent as internal standard.

Example 1N-{3-[N′-(2,2-Dimethoxyethyl)-N′-benzyl]amino-2-hydroxypropyl}-phthalimide

N-(Oxiranylmethyl)phthalimide (13.6 g, 0.067 mol, 1 eq., Fluka) wasdissolved in 260 mL (60 vols) of IMS, in a 500 mL 3-neck flask fittedwith a condenser, under a nitrogen atmosphere. N-Benzylaminoacetaldehydedimethyl acetal (13 g, 0.067 mol, 1 eq.; see, for example, Chem. Pharm.Bull. 40(2), 343 (1992)) was then added to this solution. The solutionwas then heated to reflux for twenty hours. The reaction was thenallowed cool to ambient temperature, and the solvent removed undervacuum to yield the title compound as a yellow oil. Yield=26.25 g (99%).

C₂₂H₂₆N₂O₅

LC/MS: 399 (M⁺)

Example 2 N-[(4-Benzyl-6-methoxymorpholin-2-yl)methyl]phthalimide

N-{3-[N′-(2,2-Dimethoxyethyl)-N′-benzyl]amino-2-hydroxypropyl}-phthalimide(25.5 g, 0.064 mol, 1 eq.; see Example 1 above) was dissolved indichloromethane (275 mL, 11 vols) in a 500 mL 3-neck flask, fitted witha condenser, under a nitrogen atmosphere to yield a yellow solution.

p-Toluenesulfonic acid (1.25 g, 6.4 mmol, 0.1 eq.) was then added tothis solution and the reaction heated to reflux for eighteen hours. Thereaction was allowed to cool, and was then washed with 75 mL of 1 MNaHCO₃, followed by 75 mL water. The organic layer was dried over MgSO₄,and the solvent removed under vacuum to yield the title compound as anorange oil. Yield=22.7 g, (97%).

C₂₁H₂₂N₂O₄

LC/MS: 367 (M⁺)

Example 3N-[(4-Benzyloxycarbonyl-6-methoxymorpholin-2-yl)methyl]phthalimide

N-[(4-Benzyl-6-methoxymorpholin-2-yl)methyl]phthalimide (15 g, 0.041mol, 1 eq.; see Example 2 above) was dissolved in dichloromethane (15mol, 10 vols) under nitrogen yielding an orange solution. Benzylchloroformate (15.4 mL, 0.045 mol, 1.1 eq. 50% solution in toluene) wasthen added and the reaction allowed to stir at ambient temperature overtwo days. The reaction was then diluted using 225 mL dichloromethane,and washed with NaOH (1 M, 375 mL), then water (375 mL). The organiclayer was dried over MgSO₄ and concentrated to a dark orange oil. Thiscrude product was purified using a Flash 75 Biotage™ column, elutingfrom a 3:1 iso-hexane/ethyl acetate gradient to 1:3, using 17 L ofsolvent in total. The fractions that contained product were concentratedunder vacuum to yield the title compound as an orange oil. Yield=12.8 g(76%).

C₂₂H₂₂N₂O₆

LC/MS: 411.1 (M³⁰ )

Example 4N-[(4-Benzyloxycarbonyl-2,3-dihydrooxazin-2-yl)methyl]phthalimide

N-[(4-Benzyloxycarbonyl-6-methoxymorpholin-2-yl)methyl]phthalimide (12.3g, 0.03 mol, 1 eq; see Example 3 above) was dissolved in toluene (250mL, 20 vols) in a 500 mL 3-necked flask under nitrogen. The flask wasthen fitted with a condenser and soxhlet extractor containing 3 Åmolecular sieves. p-Toluenesulfonic acid (0.58 g, 3 mmol, 0.1 eq.) wasadded to the solution, and the reaction was heated to reflux for eighthours. Analysis after this period showed that the reaction had not goneto completion. A further 0.1 eq. (0.58 g, 3 mmol, 0.1 eq.) ofp-toluenesulfonic acid was added. After a further four hours at refluxthe reaction was allowed to cool. The reaction mixture was then pouredinto saturated NaHCO₃ (aq) and separated. The aqueous layer was thenwashed with 2×250 mL dichloromethane. All the organic extracts were thencombined, dried over MgSO₄, and concentrated under vacuum to an oil.This crude product was purified using a Flash 75 Biotage™ column,eluting from a 3:1 iso-hexane/ethyl acetate solvent system, to 7:3,using 10 L of solvent. The fractions that contained product werecombined and concentrated to a colourless oil, which crystallised uponstanding to give the title compound as a colourless solid. Yield=7.4 g(65%).

C₂₁H₁₈N₂O₆

LC/MS: 379 (M⁺)

Melting point 96° C.

¹H NMR (299.946 MHz, d₆-DMSO): δ 7.92-7.84 (m), 7.43-7.34 (m), 6.25-6.21(m), 6.03 (dd, J=32.1, 4.8 Hz), 5.15 (d, J=4.0 Hz), 4.31-4.15 (m),4.00-3.76 (m), 3.33-3.23 (m).

Example 5 2-Aminomethyl-4-benzyloxycarbonyl-2,3-dihydrooxazine

N-[(4Benzyloxycarbonyl-2,3dihydrooxazin-2-yl)methyl]phthalimide (7.2 g,0.019 mol; see Example 4 above) was dissolved in a solution of hydrazine(72 mL, 10 vol, 1 M solution in THF) and stirred at ambient temperaturefor ten hours, forming a slurry of a white precipitate. The slurry wasfiltered, and the filtrate concentrated under vacuum, yielding anoff-white solid. This solid was slurried in 50 mL ethyl acetate, andthen filtered to yield the title compound as a colourless, crystallinesolid. Yield=3.66 g (93%).

C₁₃H₁₆N₂O₃

LC/MS: 249 (M⁺)

Melting point 101° C.

¹H NMR (299.944 MHz, CDCl₃): δ 7.36-7.33 (m), 6.30 (dd, J=39.1, 4.3 Hz),5.96 (dd, J=37.7,4.4 Hz), 5.18 (s), 4.04-3.92 (m), 3.33-3.20 (m), 2.97(d, J=6.0 Hz)

Example 6 2-(N-Benzylamino)methyl-4-benzyloxycarbonyl-2,3-dihydrooxazine

2-Aminomethyl-4-benzyloxycarbonyl-2,3-dihydrooxazine (3.5 g, 14.1 mmol,see Example 5 above) was suspended in methanol (35 mL) and heated to 50°C. Benzaldehyde (1.43 mL, 14.0 mmol) was added at this temperature. Themixture was heated at reflux for 30 min, allowed to cool to ambienttemperature and stirred overnight. The absence of starting material wasconfirmed by ¹H NMR spectroscopy. The mixture was heated to 50° C., anda solution of sodium borohydride (0.8 g, 21.0 mmol) in methanol (15 mL)was added over a period of 15 min. The reaction was determined to beincomplete by HPLC, so further sodium borohydride (0.8 g, 21.0 mmol) wasadded. After 1 hour the reaction was deemed to be complete by HPLC. Themixture was allowed to cool to ambient temperature and water (40 mL) wasadded. The methanol was removed by evaporation under reduced pressure,and ethyl acetate (150 mL) and water (100 mL) were added. The organiclayer was separated and washed with water (100 mL) and brine (50 mL).The combined aqueous layers were washed with ethyl acetate (100 mL). Theorganic washings were combined, dried with sodium sulphate andevaporated under reduced pressure to give a yellow oil. This crudeproduct was purified by flash column chromatography, eluting from 90:9:1to 50:49:1 iso-hexane:ethyl acetate:triethylamine, using 3 L of solvent.The product-containing fractions were evaporated under reduced pressureto give the title compound (0.68 g, 2.0 mm ol, 14%) as a colourless oil.

LC-MS: 337(M⁺)

Example 7 Benzyl7-benzyl-2-methoxy-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

2-(N-Benzylamino)methyl-4-benzyloxycarbonyl-2,3-dihydrooxazine (0.5 g,1.5 mmol, 1 eq.; see Example 6 above) was dissolved in acetonitrile,

(10 mL, 20 vols) under nitrogen, yielding a colourless solution. To thissolution, dimethoxymethane (0.4 mL, 4.4 mmol, 3 eq.) andp-toluene-sulfonic acid (0.03 g, 0.13 mmol, 0.1 eq.) were added. Thereaction was then heated to reflux. After two hours at reflux, noreaction was observed, hence the reaction was allowed to cool. Once atambient temperature, paraformaldehyde (0.54 g, 4.4 mmol, 3 eq.), andmethanol (5 mL, 10 vols) were added to form a slurry. The reaction wasthen refluxed for one hour, after which time no starting materialremained (as determined by HPLC analysis). The reaction was then cooled,the paraformaldehyde filtered off and the filtrate concentrated to anoil under vacuum. The oil product was then dissolved in ethyl acetate(100 mL), and washed with aqueous sodium bicarbonate (2×100 mL). Theaqueous extracts were washed with ethyl acetate (100 mL) and the organicwashes were then combined, dried over Na₂SO₄ and concentrated to give ayellow oil. This crude product was then purified by columnchromatography, eluting with iso-hexane/ethyl acetate (3:1) using 1 L ofsolvent. The fractions that contained product were combined andconcentrated to give the title compound as a colourless oil. Yield=0.4 g(71%).

C₂₂H₂₆N₂O₄

LC/MS: 383(M⁺)

Example 8 3-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane

Benzyl7-benzyl-2-methoxy-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(200 mg, 0.53 mmol; see Example 7 above) was dissolved in methanol (3mL, 15 vols). Pd/C (100 mg, Johnson Matthey catalyst type 87L) was thenadded to this solution washed in with 1 mL methanol. The reaction wasthen stirred under a hydrogen atmosphere, at 2 bar pressure and ambienttemperature for two hours. The reaction was removed from the hydrogenatmosphere, and filtered through Celite®, removing palladium catalystThe filtrate was then concentrated to yield the title compound as acolourless oil. Yield=110 mg (96%) C₁₃H₁₈N₂O

LC/MS: 219 (M⁺)

¹H NMR (300 MHz, D₂O): δ 7.50 (5H, s), 4.06 (2H, br s), 3.91 (2H, br s),3.50-3.61 (4H,m), 3.39 (2H, d) and 3.08 (2H, br s) Abbreviations APIatmospheric pressure ionisation (in relation to MS) br broad (inrelation to NMR) d doublet (in relation to NMR) dd doublet of doublets(in relation to NMR) Et ethyl eq. equivalents h hour(s) HPLC highperformance liquid chromatography IMS industrial methylated spirit mmultiplet (in relation to NMR) Me methyl min. minute(s) MS massspectroscopy Pd/C palladium on carbon q quartet (in relation to NMR) rtroom temperature s singlet (in relation to NMR) t triplet (in relationto NMR)Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

1. A process for the preparation of a compound of formula I,

wherein R¹ represents H, aryl or a structural fragment of formula Ia,

in which R³ represents H, halo, C₁₋₆ alkyl, —OR⁶, -E-N(R⁷)R⁸ or,together with R⁴, represents ═O; R⁴ represents H, C₁₋₆ alkyl or,together with R³, represents ═O; R⁶ represents H, C₁₋₆ alkyl, -E-aryl,-E-Het¹, —C(O)R^(9a), C(O)OR^(9b) or —C(O)N(R^(10a))R^(10b); R⁷represents H, C₁₋₆ alkyl, -E-aryl, -E-Het¹, —C(O)R^(9a), C(O)OR^(9b),S(O)₂R^(9c), [C(O)]_(p)N(R^(10a))R^(10b) or —C(NH)NH₂; R⁸ represents H,C₁₋₆ alkyl, -E-aryl or —C(O)R^(9d); R^(9a) to R^(9d) independentlyrepresent, at each occurrence, C₁₋₆ alkyl (optionally substituted and/orterminated by one or more substituents selected from halo, aryl andHet²), aryl, Het³, or R^(9a) and R^(9d) independently represent H;R^(10a) and R^(10b) independently represent, at each occurrence, H orC₁₋₆ alkyl (optionally substituted and/or terminated by one or moresubstituents selected from halo, aryl and Het⁴), aryl, Het⁵, or togetherrepresent C₃-6 alkylene, optionally interrupted by an O atom; Erepresents, at each occurrence, a direct bond or C₁₋₄ alkylene; prepresents 1 or 2; A represents -G-, -J-N(R¹¹)— or -J-O— (in whichlatter two groups, N(R¹¹)— or O— is attached to the carbon atom bearingR³ and R⁴); B represents -Z-, -Z-N(R¹²)—, —N(R¹²)-Z-, -Z-S(O)_(n)— or-Z-O— (in which latter two groups, Z is attached to the carbon atombearing R³ and R⁴); G represents a direct bond or C₁₋₆ alkylene; Jrepresents C₂₋₆ alkylene; Z represents a direct bond or C₁₋₄ alkylene;R¹¹ and R¹² independently represent H or C₁₋₆ alkyl; n represents 0, 1or 2; R⁵ represents aryl or heteroaryl, both of which groups areoptionally substituted by one or more substituents selected from —OH,cyano, halo, nitro, C₁₋₆ alkyl (optionally terminated by—N(H)C(O)OR^(13a)), C₁₋₆ alkoxy, —N(R^(14a))R^(14b), —C(O)R^(14c),—C(O)OR^(14d), —C(O)N(R^(14e))R^(14f), —N(R^(14g))C(O)R^(14h),—N(R^(14i))C(O)N(R^(14j))R^(14k), —N(R^(14m))S(O)₂R^(13b), —S(O)₂R^(13c)and/or —OS(O)₂R^(13d); R^(13a) to R^(13d) independently represent C₁₋₆alkyl; R^(14a) and R^(14b) independently represent H, C₁₋₆ alkyl ortogether represent C₃₋₆ alkylene, resulting in a four- to seven-memberednitrogen-containing ring; R^(14c) to R^(14m) independently represent Hor C₁₋₆ alkyl; Het¹ to Het⁵ independently represent, at each occurrence,five- to twelve-membered heteroaryl groups containing one or moreheteroatoms selected from oxygen, nitrogen and/or sulfur, whichheterocyclic groups are optionally substituted by one or moresubstituents selected from ═O, —OH, cyano, halo, nitro, C₁₋₆ alkyl, C₁₋₆alkoxy, aryl, aryloxy, N(R^(15a))R^(15b), —C(O)R^(15c), —C(O)OR^(15d),—C(O)N(R^(15c))R^(15f), —N(R^(15g))C(O)R^(15h) and—N(R^(15i))S(O)₂R^(15j); R^(15a) to R^(15j) independently representC₁₋₆alkyl, aryl or R^(15a) to R^(15j) independently represent H; andwherein each aryl and aryloxy group, unless otherwise specified, isoptionally substituted; provided that: (a) when R⁴ represents H or C₁₋₄alkyl; and A represents -J-N(R¹¹) or -J-O—; then B does not represent—N(R¹²)—, —S(O)_(n)—, —O— or —N(R¹²)-Z- (in which latter group —N(R¹²)is attached to the carbon atom bearing R³ and R⁴); (b) when R³represents —OR⁶ or -E-N(R⁷)R⁸ in which E represents a direct bond, then:(i) A does not represent a direct bond, -J-N(R¹¹)— or -J-O—; and (ii) Bdoes not represent —N(R¹²)—, —S(O)_(n)—, —O— or —N(R¹²)-Z- (in whichlatter group —N(R¹²) is attached to the carbon atom bearing R³ and R⁴);(c) when A represents a direct bond, then R³ and R⁴ do not togetherrepresent ═O; R² represents an electron withdrawing amino protectinggroup; and R^(a) represents C₁₋₄ alkyl or benzyl, which processcomprises reaction of a compound of formula II,

wherein R¹ and R² are as defined above, with either: (a) a formaldehydeand a compound of formula III,R^(a)—OH   III wherein R^(a) is as defined above; and/or (b) a protectedderivative of a formaldehyde.
 2. A process as claimed in claim 1,wherein R² is a benzyloxycarbonyl group.
 3. A process as claimed inclaim 1, wherein the formaldehyde is paraformaldehyde.
 4. A process asclaimed in claim 1 wherein R¹ represents a structural fragment offormula Ia.
 5. A process as claimed in claim 1 wherein R³ represents Hor —OH.
 6. A process as claimed in claim 1 wherein R⁴ represents H.
 7. Aprocess as claimed in claim 1 wherein A represents a direct bond ormethylene.
 8. A process as claimed in claim 1 wherein B represents -Z-,-Z- N(H)— or -Z-O—.
 9. A process as claimed in claim 8, wherein Brepresents a single bond.
 10. A process as claimed in claim 1 wherein R⁵represents phenyl, which latter group is optionally substituted bycyano.
 11. A process as claimed in claim 10, wherein R⁵ representsunsubstituted phenyl.
 12. A process as claimed in claim 1 wherein R¹represents benzyl.
 13. A process as claimed in claim 1 wherein R^(a)represents methyl.
 14. A process as claimed in claim 1 wherein thereaction is carried out in the presence of acetonitrile, a C₁₋₄ alkylalcohol, toluene or a mixture thereof.
 15. A process as claimed in claim1 wherein the reaction is carried out in the presence ofp-toluenesulfonic acid.
 16. A process as claimed in claim 1, wherein thereaction is carried out at reflux temperature.
 17. A process as claimedin claim 1 wherein the reaction is carried out using one or moreequivalents (relative to the compound of formula II) of theformaldehyde.
 18. A process as claimed in claim 1 wherein the reactionis carried out using one or more equivalents (relative to the compoundof formula II) of the compound of formula III.
 19. A process as claimedin claim 1 wherein the reaction is carried out by reacting the compoundof formula II with one or more equivalents of the formaldehyde, in thepresence of an excess of a compound of formula III.
 20. A process asclaimed in claim 1 wherein the compound of formula II is prepared byelimination of R^(b)OH from a compound of formula IV,

wherein R^(1a) represents an aryl group, a structural fragment offormula Ia as hereinbefore defined, an electron withdrawing aminoprotecting group as hereinbefore defined, or, together with R^(1b),represents a cyclic amino protecting group; R^(1b) represents anelectron withdrawing amino protecting group as hereinbefore defined, or,together with R^(1a), represents a cyclic amino protecting group; R^(b)represents C₁₋₄ alkyl; and R² is as defined in claim 1, followed bydeprotection (as necessary) of the nitrogen atom to which the groupsR^(1a) and R^(1b) are attached.
 21. A process for the formation of acompound of formula II as defined in claim 1, which process compriseselimination of R^(b)OH from a compound of formula IV,

wherein R^(1a) represents an aryl group, a structural fragment offormula Ia as hereinbefore defined, an electron withdrawing aminoprotecting group as hereinbefore defined, or, together with R^(1b),represents a cyclic amino protecting group; R^(1b) represents anelectron withdrawing amino protecting group as hereinbefore defined, or,together with R^(1a), represents a cyclic amino protecting group; R^(b)represents C₁₋₄ alkyl; and R² is as defined in claim 1, followed bydeprotection (as necessary) of the nitrogen atom to which the groupsR^(1a) and R^(1b) are attached.
 22. A process as claimed in claim 20,wherein the elimination is carried out on a compound of formula IV inwhich R^(1a) and R^(1b) together represent a cyclic amino protectinggroup.
 23. A process as claimed in claim 20, wherein the cyclic aminoprotecting group forms a phthalimide group with the nitrogen atom towhich R^(1a) and R^(1b) are attached.
 24. A process as claimed in claim20, wherein R² represents benzyloxycarbonyl.
 25. A process as claimed inclaim 20, wherein R^(b) represents methyl.
 26. A process as claimed inclaim 20, wherein the elimination process is carried out in the presenceof toluene.
 27. A process as claimed in claim 20, wherein theelimination process is carried out in the presence of p-toluenesulfonicacid.
 28. A process as claimed in claim 20, wherein the eliminationprocess is carried out at elevated temperature.
 29. A process as claimedin claim 20, wherein the elimination process is carried out in thepresence of an alcohol sorbing agent.
 30. A process as claimed in claim20, wherein R^(1a) and R^(1b) together represent a cyclic aminoprotecting group, and the deprotection is carried out by way of reactionwith hydrazine.
 31. A process as claimed in claim 20, wherein thedeprotection is thereafter followed by reaction of the deprotected aminewith a compound that provides the aryl group or the structural fragmentof formula Ia.
 32. A process as claimed in claim 31, wherein thereaction is carried out by reaction of a compound of formula II in whichR¹ represents H with a compound of formula V,R⁵BC(R³)(R⁴)AL¹   V wherein L¹ represents a suitable leaving group andA, B, R³, R⁴ and R⁵ are as defined in claim
 1. 33. A process as claimedin claim 31, wherein the reaction is carried out to provide a compoundof formula II in which R¹ is benzyl by reaction of a compound of formulaII in which R¹ represents H with benzaldehyde followed by reduction ofthe resultant intermediate.
 34. A process as claimed in claim 20 whereinthe compound of formula IV is prepared by cyclisation of a compound offormula VI,

wherein R^(2a) represents an amino protecting group; and R^(1a), R^(1b)and R^(b) are as defined in claim
 20. 35. A process for the formation ofa compound of formula IV as defined in claim 20, which process comprisescyclisation of a compound of formula VI,

wherein R^(2a) represents an amino protecting group; and R^(1a), R^(1b)band R^(b) are as defined in claim
 20. 36. A process as claimed in claim34, wherein R^(2a) represents C₁₋₃ alkylphenyl.
 37. A process as claimedin claim 36, wherein R^(2a) represents benzyl.
 38. A process as claimedin claim 34, wherein the cyclisation process is followed by replacementof the group R^(2a) with a group R² as defined in claim
 1. 39. A processas claimed in claim 38, wherein the group R² representsbenzyloxycarbonyl.
 40. A process as claimed in claim 34 wherein thecompound of formula VI is prepared by reaction of a compound of formulaVII,

wherein R^(1a) and R^(1b) are as defined in claim 20, with a compound offormula VIII,

wherein R^(2a) is as defined in claim 34 and R^(b) is as defined inclaim
 20. 41. A process for the formation of a compound of formula VI asdefined in claim 34, which process comprises reaction of a compound offormula VII,

wherein R^(1a) and R^(1b) are as defined in claim 20, with a compound offormula VIII,

wherein R^(2a) is as defined in claim 34 and R^(b) is as defined inclaim
 20. 42. A process for the preparation of a compound of formula IX,

wherein R^(2b) represents H or R² and R¹ and R² are as defined in claim1, which process comprises preparation of a compound of formula I asclaimed in claim 1, followed by reduction the compound of formula I soformed.
 43. A process for the preparation of a compound of formula IX,

wherein R^(2b) represents H or R² and R¹ and R² are as defined in claim1, which process comprises reduction a compound of formula I as definedin claim
 1. 44. A process as claimed in claim 42 wherein, in thecompound of formula IX, R^(1b) is H.
 45. A process as claimed in claim42, wherein R¹ represents benzyl.
 46. A process as claimed in claim 42,wherein the reduction is carried out in the presence of a hydrogenationcatalyst in the presence of hydrogen.
 47. A process as claimed in claim42, wherein either or both of the groups R¹ and (if present) R^(2b) areremoved, simultaneously and/or sequentially, and the resultant compoundis subsequently reacted with reagents to form any one of:4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)benzonitrile;tert-butyl 2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]-non-3-yl}ethylcarbamate; tert-butyl2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate;or tert-butyl2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-di-azabicyclo[3.3.1]non-3-yl}ethylcarbamate.48. A compound of formula II as defined in claim 1 or a protectedderivative thereof.
 49. A compound of formula IV as defined in claim 20or a protected derivative thereof.
 50. A compound of formula VI asdefined in claim 34 or a protected derivative thereof.